Pyridyl carbamyl lower alkane derivatives: analgesic process



3 039,930 PYRlDYL CARBAMYL LOWER ALKANE DERIVA- TIVES: ANALGESIC PROCESSAllan Poe Gray, Decatur, 111., assignor to Irwin, Neisler and Co.,Decatur, 111., a corporation of Illinois No Drawing. Filed Apr. 6, 1960,Ser. No. 20,266 12 Claims. (Cl. 16765) This invention relates to aprocess for relieving pain,

and is more especially concerned with a process for relieving pain inanimals by the administration thereto of a pyridyl carbamyl lower alkanederivative.

This application is a continuation-in-part of my application Serial No.771,737, filed November 4, 1958, now abandoned, entitled PyridylCarbamyl Lower Alkane Derivatives and Processes.

The instant invention is bottomed on the unexpected finding that certainchemical compounds, hereinafter described, exhibit analgesic activitywhen administered to the animal organism. These compounds also exhibitmuscle relaxant activity (which is not of a curare-like nature but whichresults from interneuronal blockade and is manifested as a relaxation oftensed muscle) which supplements their general analgesic activity andgives them a broader pharmacodynamic basis of providing relief frompain.

The compounds useful in the process of the present invention have amolecular structurein which there is attached to the same carbon atom ofan N-substitutedcarbamyl lower-alkane chain both a hydroxy radical or alower-acyloxy group and at least one monocarbocyclic group; said carbonatom to which such groups are attached being separated by at least thecarbonyl carbon atom of the carbamyl group from the carbamyl nitrogenatom; wherein one of the N-substituents is a pyridyl moiety joined tothe carbamyl nitrogen atom through a ring carbon atom of the pyridylring; and, wherein the other N-substituent is a lower-alkyl group wherethe carbamyl nitrogen atom is -iii-substituted. The compounds useful inthe process of the instant invention include the acid-addition salts ofsuch substituted carbamyl loweralkanes, the embodiments of such saltsbeing functionally equivalent to the free bases and in fact constitutinganother pharmaceutically acceptable form of the compounds.

Definitions of terms:

The term lower alkanes, as used herein, includes lower alkanes having 1to 4 carbon atoms inclusive, as methane, ethane, propane, and butane,including both straight and branched-chain structural isomers thereof.

The term lower-alky as used herein, means alkyl groups having from 1 to6 carbon atoms inclusive and is illustrated as by methyl, ethyl,n-propyl, isopropyl, et cetera.

The term lower-acyloxy, as used herein, includes alkanoyloxy groups asformoxy, acetoxy, propionyloxy, butyryloxy; carbamyloxy;N-lower-alkyl-substituted carbamyloxy groups as N-methylcarbamyloxy,N-ethylc'arbamyloxy, N-propylcarbamyloxy, N-butylcarbamyloxy;N,N-di-lower-alkyl substituted carbamyloxy groups as N,Ndimethylcarbamyloxy, N,N diethylcarbamyloxy, N,N-dipropylcarbamyloxy, etcetera.

The term monocarbocyclic group, as used herein, in-

Unitcd States Patent 3,039,930 Patented June 19, 1962 eludes simplesubstituted and unsubstituted mono-cyclichydrocarbyl groups includingaryl groups as phenyl, tolyl, lower alkoxyphenyl groups asp-methoxyphenyl; halogensubstituted phenyl groups as o-chloro-phenyl,p-bromophenyl; aralkyl groups as benzyl, beta phenylethyl,pmethylbenzyl; cycloalkyl groups as cyclohexyl, p-methylcyclo-hexyl; etcetera.

The term pyridyl moiety, as used herein, means the unsubstituted pyridylring and such ring bearing one or more simple substituents which do notadversely afiect the pharmacological properties of the compound such asa halogen atom, the methyl, methoxy, nitro, amino, trifluoromethyl, andother groups commonly used in the art as substituents on the pyridylring in preparing chemical compounds having varying pharmacologicaleffects in animals. Such substituents can be introduced in any of thepositions of the ring otherwise occupied by a hydrogen atom.

The pyridyl carbamyl alkane derivative useful for the process of theinvention can be prepared as follows: (1) reacting by heating amono-carbocyclic-hydroxy-loweralkanoic acid with an aminopyn'dine aloneor in a solvent inert to the reactants to form the pyridyl carbamylalkane derivative: (2) reacting a lower alkyl ester of amonocarhocyclic-hydroxy-lower alkanoic acid with an aminopyridine toform the pyridyl carbamyl alkane derivative; and, (3) reacting amono-carbocyclic lower-acyloxylower-alkanoyl chloride with anaminopyridine to form the pyridyl carbamyl alkane derivative.

The pharmaceutically acceptable non-toxic, acid addition salts of theabove compounds can be prepared in conventional manner by reacting apyridyl carbamyl alkane derivative, as set forth above, with the usualinorganic acids, as for example, hydrochloric, hydrobromic, hydriodicand sulfuric; or an organic acid as, for example, acetic, mucic,salicyclic, citric, et cetera,

To aid in an understanding of the free base compounds usable in theprocess of the invention, the pyridyl carbamyl alkane derivativesreferred to above are illustrated by the following formula:

hydrogen hydroxy or loweror lower alkyl group acyloxy group PyridylmoietyN fiLower alkanemonocarbocyclic group Fit 2. flask with a moisturetrap. Place in the flask 18.8 grams (0.2 mole) of Z-aminopyridine, 30.4grams (0.2 mole) of dl-mandelic acid and milliliters of xylene to form amixture. Place an oil-bath around the flask. Reflux the reaction mixturefor 20 hours bymaintaining the oil-bath temperature at -170 degreescentigrade. During the 20 hour period, 3.2 milliliters (90 percentyield) of water collects in the moisture trap and an orange solutionforms in the reaction flask. Cool the orange solution in the flask toprecipitate a thick oil which partially crystallizes. Dilute the mixtureof precipitate and solution with benzene. Filter the mixture to separate23.2 grams of bright yellow crystals, melting at 117-119 degreescentigrade, from the benzene-xylene mother liquor. Recrystallize thesecrystals from aqueous ethanol to produce 20.0 grams of long, flat,almost colorless To one molar equivalent of the baseZ-benzilamidopyridine in ethanol, add more than one molar equivalent ofhydrogen chloride dissolved in ether. Recrystallize the resultantprecipitate from ethanol to yield Z-benzilamidoneedle-shaped crystalsmelting at 119.5-121 degrees 5 pyridine hydrochloride having a meltingpoint of 205 centigrade. Extract the original benzene-xylene motherdegrees centigrade. Analyze a portion of the hydroliquor with diluteaqueous acid. Make the separated chloride salt as follows:

aqueous portion alkaline and extract it with ether. Dry

the separated ether portion. Remove the ether from the Percent by weightether portion by distillation. The residue left after removal of theether is an oil which crystallizes on standing. Carbon Hydrogen IonicRecrystallize these crystals from aqueous ethanol to yield 1110mm anadditional 6.15 grams of product melting at 118-121 degrees centigrade.Add this portion of product to the Analysix 0.1 1 t (1..-. 66. 96 .031040 original 20.0 gram portion to achieve a total yield of 26.1 Fzu r ld if 67.41 2.09 10. 35 grams of Z-mandelamido-pyridine (57 percentyield),

Analyze a portion of the product as follows: XA 3 4. (QACETYLMANDELAi\/HDQ) b Anuggzsr fiCalccllllaegg Nltl'OgBI (basicg 6.14percent PYRIDINE y wen t. oun percent y welg t.

To one molar equivalent of the base Z-mandelarnidom a macho? flask grams(0'12 F1016) of pyridine in ethanol add more than one molar equivalentaceiylmaridfflyl ch1onde 11'1 grams (9'12 mole) of of hydrogen chloridedissolved in ether. Recrystaiiize 3 and.25 glams. 1 male) of fi theresultant precipitate from a solvent mixture of methasodnmm calbonate m100 {Dimmers f mt a 1101 and ether to form colorless crystals ofZ-mandeiamido- Steamibath around the F Q flask Heat the pyridinehydrochloride, melting at 182-184 degrees centi- 25 bath to rfiiflux h{mme f 53 grade the reaction mixture occasionally during this period.

Analyze a portion of the Product as follows. Cool the mixture and washit with water. Separate the water layer from the benzene layer. Extractthe water Pe centb Wei ht layer with fresh benzene. Separate the freshbenzene r y g layer from the water layer. Combine the fresh benzeneCarbon Hvdw en Ionic portion with the original benzene portion. Dry thiscomg chlorine bined benzene solution and concentrate it by distillationin vacuo to yield 17.0 grams (53 percent yield) of prod- Analysis: uct,4-(O-acetylmandelamido)-pyridine as a light yellow ggif i 23' :1- i2 oilresidue after distillation of the benzene from the solution. Cool theyellow oil to produce its solidification to a glass. r I

EXAMPLE 2 gig ggggg g AND The following Table I illustrates thepreparation of other pyridyl car-bamyl alkane derivatives useful in theDissolve 15.0 grams (0.16 mole) of Z-amino-pyridine 4Q process of theinvention. The procedure used is analoand 39.0 grams (0.16 mole) ofmethyl benzilate in gous to that employed in the foregoing example whosemilliliters of dry xylene in a flask. Add 0.5 gram of number is listedin the column entitled Method in metallic sodium. Fit an oil-bath aroundthe reaction Table I.

Table I Carbon, Hydrogen Ionic chlorine, Basic nitrogen, Melting percentby percent by percent by percent by Ex Compound glgirgeegs Method weightweight weight weight 7 centigrade Oalcu- Found Oalou- Found Calcu- FoundCalcu- Found lated lated lated lated 4---. 2-mandelamido-4-picoline143-146 1 5. 78 5. 72 Hydrochloride salt 188-189 5----GunmdelamldoQ-i-lutidina. 167-169 Hydrochloride salt 195-196 66-mandelamido-3-picoline 141-142 Hydrochloride salt 20 7--.-2-mandelamido-5 chiorop 146-148 Hydrochloride salt 8---.2-mandelamido-5-bromo-pyridine -156 Hydrochloride salt. 9.".2-(hexahydrornandelamido)pyridine 118-129 2-(O-acetylmandelamido)-3,fi-dibromopyridine O 11. Z-mandelamido-S-aminopyridine hydrochlorid201-202 Cal- Most of the compounds useful in the process of the presentinvention are novel, however some are old e.g., the compounds2-amino-6-(acetyl-rnandelamido) -pyridine and2-amino-6-mandeiamido-pyridine are disclosed in Lott et al., US. Patent2,461,119 for'uses unrelated to the instant analgesic process.

The compounds useful in the process of the present invention not onlyhave analgesic properties, but also have muscle relaxant properties. Thefollowing pharmacological tests illustrate the general effectiveness ofthese 75 compounds;

The following typical compounds useful in the analgesic process of thepresent invention were tested.

2-mandelamido-6-aminopyridine hydrochloride E The above compounds weretested by the following lntemeuronal bl0ckadedOg0.This type of activity(skeletal muscle relaxation) is evaluated by determining the effect of acompound on two reflexes, both of which require polysynaptictransmission of impulses. The reflexes used are the flexor (F .R. orhind leg twitch) and the lingucmandibular (L.M. or jaw closure).Experimental preparations using both pentobarbital anesthetized anddecerebrate dogs are employed. Also, the motor nerve is stimulateddirectly to be certain that any relaxation is not test procedures: aresult of blockade at the neuromuscular junction.

Results obtained with Test conducted A B o D E I.V 133 66 325 Acutetoxicity, mice, LD rug/k LP 345 855 630 775 P.O 2, 125 1, 250

Inclined screen, ED50, mg./kg., I.V. 81

2. 5 16 p 7 5 2s Analgesic, mice, percent increase in reaction timeLED-{$3 3g 10 in) 31 30C?) 0 Analgesic, rabbits, percent increase in R(5 rug/kg, I.V.) 1g

Righting reflex, PDtu, mg.lkg., I.P 10D Interneuron. blockade, o-t+ 2amg./kg., I.V.) j *I QL 3. 11 1 EXPLANATION OF TEST PROwDURES Acutet0xicitymiCe.-The compounds are administered to groups of 5 mice ingraded doses and the num- '35 ber of deaths recorded; The dose whichshould kill 50 percent of the animals is calculated using the method ofBehrens and Kiirber.

In'clz'ned screen-4nice-Essentially the same as above except thatinstead of death the endpoint of this test is the inability of theanimal to remain on an inclined screen.

Analgesic-mice.--The test is based on time of reaction to a stimulusproduced by radiant heat employing the Conduction Dolorimeter. The hindfoot of the mouse is used as the test organ. Groups of 20 mice aretreated with the test compound and their average reaction time to thestimulus is compared with that of control groups tested concurrently.The degree of analgesic activity is related to the percent increase inreaction time to the stimulus. (Evaluation of data from groups ofcontrol mice showed that an average increase in reaction time of 14percent would be highly significant-P: 0.01.)

Analgesicrabbits.This test is based on suppression of the response topain resulting from electrical stimulation of the tooth pulp. The painis produced by electrical shocks delivered through shielded springelectrodes which are inserted into holes drilled in each of the tWoupper teeth. The voltage is varied and when the stimulus reaches apainful intensity, the rabbit reacts by wiggling its nose and upper lip.Since all determinations are 60 carried out in quadruplicate, it ispossible to calculate an R value R =the voltage at which the rabbitresponds to pain 50 percent of the time). Each animal is tested priorto, and at 30, 90 and 150 minutes after, administration of the drug. Thedegree of analgesic activity is based on the percent change between thepre and post treatment R values.

Righting reflexmice.This test measures the ability of a compound tocause an animal to lose its righting reflex and can be an indication ofeither a music relaxant or sedative action. The compound is administeredintraperitcneally in graded doses to groups of 5 mice and the. resultsare expressed as P13 (the dose, mg./kg., which causes a loss of therighting reflex in 50 percent of the animals).

The explanation of the abbreviations used in the above table is asfollows:

Abbreviation: Meaning I.V Intravenous.

LP Intraperitoneal.

R0 Peroral.

F.R Flexor reflex.

L.M Linguo-mandibular reflex.

1- Means stimulation rather than blockade.

Mg/kg Milligrams per kilogram of body weight.

While the compounds useful for the analgesic process of the presentinvention may be administered to the animal organism intravenously orintraperitoneally, it is contemplated that the preferred method ofadministration Will be oral. For oral administration, they may beconveniently administered in the 'form of essentially pure undilutedcompounds desired, such as in a gelatin capsule. Preferably, for ease ofhandling the compounds will be used in intimate association with apharmaceutical carrier, which may be either a liquid or a solid. When aliquid, it may form solutions or suspensions of the compounds. Flavoringsubstances may be included as desired. Sterile Water is the preferredliquid carrier, since it readily dissolves the salt forms of thecompounds. Solid pharmaceutical carrier such as starch, sugar, talc andthe like may be used to form powders. Such powders may be tabletcd bythe use of suitable lubricants such as magnesium stearate, binders suchas gelatin and disintegrating agents like sodium bicarbonate incombination with citric or tartaric acid. The powders may also be usedto fill gelatin capsules. The compounds useful in the analgesic processof the present invention may be formed in unit dosages containingpredetermined amounts of the useful compounds which may then beadministered one or more at a. time at regular time intervals to createand maintain eflective body levels of the useful compound. Suggestedunit dosages for larger animals are 50 to 400 milligrams ofusefulcompounds per tablet or capsule, or a solution of elixir containing 50to 200 milligrams of useful compound per teaspoonful.

The compounds useful in the analgesic process of the instant inventionmay, if desired, be combined with other therapeutic agents used to treatconditions causing pain e.g. with conventional antinheumatic,anti-inflammatory and antipyretic agents such as anti-inflammatorysteroids, salicylates, sedatives, antihistaminics, etc. The dosage ofthe therapeutic agent would be that normally used for the specific drug.7

The invention can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingphysical embodiments of my analgesic process are therefore to beconsidered in all respects illustrative and not restrictive, the scopeof the invention being indicated by the appended claims rather than bythe foregoing description, and all changes which come within the meaningand range of equivalency of the claims are therefore intended to beembraced therein.

I claim: 7

1. The process of producing analgesia in animals which comprisesintroducing into the animal organisms 50 to 400 milligrams of apharmaceutically acceptable form of a compound selected from the groupconsisting of monoand di-N-suhstituted carbamyl lower alkanes havingattached to the same carbon atom of the alkane chain both a groupselected from the class consisting of hydroXy, lower-alkanoyloxy, andcarbamyloxy radicals, and at least one monocarbocyclic group; saidcarbon atom being separated by at least the carbonyl-carbon atom of thecarbamyl group from the carbamyl nitrogen atom; wherein one of theN-substituents is a pyridyl moiety joined to the carbamyl nitrogen atomthrough a ring carbon atom of the pyridyl ring; and, wherein the otherN-su-bstituent is a lower-alkyl group where the carbamyl nitrogen isdisubstituted.

2. The process of claim 1 wherein the N-substituted carbamyl alkane is4-(O-acetylmandelamido)-pyridine.

3. The process of producing analgesia in animals which comprises orallyintroducing into the animal organism 50 to 400 milligrams of apharmaceutically acceptable form of an N-substituted carbamyl loweralkane having attached to the same carbon atom of the alkane chain botha hydroxy radical and at least one mono-cyclic-hydrocarbyl group; saidcarbon atom being separated by at least the carbonyl-carbon atom of thecarbamyl group from the carbamyl-nitrogen atom; and wherein the N-substituent is a pyridyl moiety joined to the carbamyl nitrogen atomthrough a ring-carbon atom of the pyridyl ring.

4. The process of producing analgesia in animals which comprises orallyadministering to 400 milligrams of a pharmaceutical-1y acceptable formof an N-substituted carbamyl methane having attached to the methanecarbon atom both a hydroxy group and at least one monocyclichydrocarbylgroup; wherein the -N-substituent is a pyridyl moiety joined to thecarbamyl nitrogen atom through a ring-carbon atom of the pyridyl ring,to said animal.

5. The process of claim 4 wherein the N-substituted carbamyl methane isZ-mandelamido-py-ridine.

6. The process of claim 4 wherein the N-substituted carbamyl methane isZ-benzilamido-pyridine.

7. The process of claim 4 wherein the N-substituted carbamyl methane is2-mandelamido-4-picoline.

8. The process of claim 4 wherein the N-substituted carbamyl methane is6-mandelamido-2,4-lutidine.

9. The process of claim4 wherein the N-substituted carbamyl methane isZ-mandelamido-S-ch1oropyridine.

10. The process of claim 4 wherein the N-substituted carbamyl methane isZ-(hexahydromandelamido)-pyridine.

11. The process of claim 4 wherein the N-substituted carbamyl methane is6-mandelarnido-3-picoline.

12. The process of claim 4 wherein the N-su-bstituted carbamyl methaneis Z-mandelamido-S-bromo-pyridine.

OTHER REFERENCES Lott et al.: Chem. AbSL, 43, p. 3853 1949.

1. THE PROCESS OF PRODUCING ANALGESIA IN ANIMALS WHICH COMPRISESINTRODUCING INTO THE ANIMAL ORGANISMS 50 TO 400 MILLIGRAMS OF APHARMACEUTICALLY ACCEPTABLE FORM OF A COMPOUND SELECTED FROM THE GROUPCONSISTING OF MONOAND DI-N-SUBSTITUTED CARBAMYL LOWER ALKANES HAVINGATTACHED TO THE SAME CARBON ATOM OF THE ALKANE CHAIN BOTH A GROUPSELECTED FROM THE CLASS CONSISTING OF HYDROXY, LOWER-ALKANOYLOXY, ANDCARBAMYLOXY RADICALS, AND AT LEAST ONE MONOCARBOCYCLIC GROUP; SAIDCARBON ATOM BEING SEPARATED BY AT LEAST THE CARBONYL-CARBON ATOM OF THECARBAMYL GROUP FROM THE CARBAMYL NITROGEN ATOM; WHEREIN ONE OF THEN-SUBSTITUENTS IS A PYRIDYL MOIETY JOINED TO THE CARBAMYL NITROGEN ATOMTHROUGH A RING CARBON ATOM OF THE PYRIDYL RING; AND, WHEREIN THE OTHERN-SUBSTITUENT IS A LOWER-ALKYL GROUP WHERE THE CARBAMYL NITROGEN ISDISUBSTITUTED.